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US20040028635A1 - Block-structure copolymer consisting of a saccharide segment bound to at least a biodegradable hydrophobic segment, and corresponding particles - Google Patents

Block-structure copolymer consisting of a saccharide segment bound to at least a biodegradable hydrophobic segment, and corresponding particles Download PDF

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Publication number
US20040028635A1
US20040028635A1 US10/416,840 US41684003A US2004028635A1 US 20040028635 A1 US20040028635 A1 US 20040028635A1 US 41684003 A US41684003 A US 41684003A US 2004028635 A1 US2004028635 A1 US 2004028635A1
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Prior art keywords
radical
copolymer
segment
poly
particles
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Abandoned
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US10/416,840
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English (en)
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Cedric Chauvierre
Patrick Couvreur
Denis Labarre
Christine Vauthier
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Centre National de la Recherche Scientifique CNRS
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Individual
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Assigned to CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (C.N.R.S) reassignment CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (C.N.R.S) ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHAUVIERRE, CEDRIC, COUVREUR, PATRICK, LABARRE, DENIS, VAUTHIER, CHRISTINE
Publication of US20040028635A1 publication Critical patent/US20040028635A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers

Definitions

  • the invention relates to a novel family of biodegradable copolymers based on a polymer of alkyl cyanoacrylate or related type and on poly- or oligosaccharides, which are particularly useful in the pharmaceutical, veterinary, food-processing and cosmetic fields, in particular as vehicles and/or excipients. It also provides a process for preparing these copolymers.
  • the present invention is targeted specifically at compensating for the abovementioned disadvantages and at providing a novel material for particles, the polymer structure of which derives from the combination with a polymer related to poly(alkyl cyanoacrylate) of a segment of poly- or oligosaccharide nature, such as dextran, for example.
  • the present invention is targeted, for its part, at providing copolymers deriving from cyanoacrylate or equivalent monomers and from oligo- or polysaccharides but having a completely different structure.
  • the copolymers are provided in a block form, in contrast to the grafted forms described above. This block form is in fact inaccessible by the anionic polymerization route discussed above.
  • a first subject matter of the present invention is a copolymer comprising a block structure composed of a hydrophilic segment of saccharide nature, at least one of the ends of which is bonded to a biodegradable hydrophobic segment of general formula (I):
  • segment of saccharide nature being bonded either by one of its ends to a single segment of general formula (I) or by each of its two ends to a segment of general formula (I), the two hydrophobic segments being identical or different.
  • X preferably represents a CN radical. More preferably, Y represents a COOR′ radical with R′ as defined above.
  • the covalent bond established between the two types of segment is generally of C—C or C—O—C nature. It preferably derives from the radical polymerization of at least one molecule of a compound of formula (II):
  • This radical polymerization is preferably carried out under the conditions set out below for the claimed process.
  • the polysaccharides which are very particularly suitable in the invention are or derive from D-glucose (cellulose, starch, dextran, cyclodextrin), D-galactose, D-mannose, D-fructose (galactosan, mannan, fructosan) or fucose (fucan).
  • D-glucose cellulose, starch, dextran, cyclodextrin
  • D-galactose D-mannose
  • D-fructose galactosan, mannan, fructosan
  • fucose fucose
  • hyaluronic acid (composed of N-acetylglucosamine and glucuronic acid units), poly(sialic acid), also known as colominic acid or poly(N-acetylneuraminic acid), chitosan, chitin, heparin or orosomucoid comprise nitrogen
  • agar a polysaccharide extracted from marine algae, comprises sulfur in the form of hydrogen sulfate (>CH—O—SO 3 H).
  • Chondroitin sulfuric acid and heparin comprise both sulfur and nitrogen.
  • n varies between 10 and 620 and preferably between 33 and 220.
  • the molar mass varies between 5 ⁇ 10 3 and 5 ⁇ 106 g/mol, preferably between 5 ⁇ 1 and 2 ⁇ 10 6 g/mol.
  • the molar mass varies between 6 ⁇ 10 3 and 6 ⁇ 10 5 g/mol, preferably between 6 ⁇ 10 3 and 15 ⁇ 10 4 g/mol.
  • Dextran, heparin, poly(N-acetylneuraminic acid), amylose, chitosan, pectin and hyaluronic acid, and their derivatives, are more particularly preferred.
  • the copolymers advantageously have a controlled content of oligo- or polysaccharide.
  • the claimed copolymer can be provided in a soluble form or under the appearance of a precipitate, of micelles or of particles. According to an advantageous aspect of the invention, it is provided under the appearance of particles. They can be micro- or nanoparticles.
  • the copolymer has a structure arranged as follows: the chains of the same nature, that is to say saccharide or hydrophobic chains, group together, either to form the core structure of the micelle or particle or the brush-like ring around this core structure.
  • Their distribution between the core structure and the ring will, of course, depend on the nature, aqueous or organic, of the solvent in which the particles or micelles are dispersed.
  • the term “brush-like ring” is intended to denote a structure in which the segments constituting the ring are bonded via one of their ends to the segments constituting the core. Their free ends constitute the periphery of the ring.
  • this brush-like ring structure cannot exist in an aqueous medium, insofar as several hydrophobic segments are covalently bonded to a single chain of saccharide nature.
  • a second aspect of the invention relates to particles composed of a copolymer in accordance with the invention.
  • the claimed particles can have a size of between 1 nm and 1 mm and preferably between 60 nm and 100 ⁇ m.
  • the particles having a size of between 1 and 1000 nm are then known as nanoparticles.
  • Microparticles refer to particles with a size varying from 1 to several thousand microns.
  • These particles can, in some cases, be provided in an aggregated or micellar form.
  • the particles resulting from the polymerization of isobutyl cyanoacrylate in the presence of ⁇ -cyclodextrin have an aggregated appearance.
  • These particles can possess a biological activity, either because of the nature of the polysaccharide from which they are formed or because they additionally incorporate a biological or pharmaceutical active material.
  • the particles can thus be substances detectable by X-rays, fluorescence, ultrasound, nuclear magnetic resonance or radioactivity.
  • the particles can thus include magnetic particles, radio-opaque materials (such as, for example, air or barium) or fluorescent compounds.
  • fluorescent compounds such as rhodamine or nile red
  • gamma emitters for example, indium or technetium
  • Hydrophilic fluorescent compounds can also be charged to the particles but with a reduced efficiency in comparison with the hydrophobic compounds, because of their low affinity with the matrix.
  • these particles can be combined with peptides/proteins capable of helping them diffuse through biological membranes, such as the TAT peptide, or compounds such as the ZOT ( Zonula occludens Toxin) protein and zonulin or equivalents, or any other absorption promoter.
  • biological membranes such as the TAT peptide, or compounds such as the ZOT ( Zonula occludens Toxin) protein and zonulin or equivalents, or any other absorption promoter.
  • this type of combination can be prepared by chemical functionalization of the polysaccharide surface of the particles. It is thus possible to envisage covalently attaching, at functional groups present on the backbone of saccharide nature, specific ligands, such as targeting agents, labels or, more generally, any compound capable of conferring on said particles a capability of reacting with an external species, such as, for example, a functional group on a support or a biological entity present in a medium under consideration.
  • the active material can be incorporated in these particles during their process of formation or, in contrast, can be charged to the particles once the latter are obtained. It is thus possible to charge them by adsorption or by covalent grafting.
  • the particles according to the invention can be administered in different ways, for example, by the oral, parenteral, ocular, pulmonary, nasal, vaginal, cutaneous or buccal routes, and the like.
  • the noninvasive oral route is a route of choice.
  • Another subject matter of the present invention is the use of the particles as vehicle for pharmaceutical, cosmetic, food-processing or veterinary active principles.
  • a third aspect of the present invention relates to a process for the preparation of the claimed copolymer.
  • the present invention is targeted at a process of use in the preparation of block copolymers composed of a hydrophilic segment of saccharide nature, at least one of the ends of which is bonded to a hydrophobic segment, characterized in that it comprises the polymerization by the radical route of at least one molecule of a compound of general formula (II):
  • X represents a CN or CONHR radical
  • Y represents a COOR′ or COHNR′′ radical
  • R, R′ and R′′ representing, independently of one another, a hydrogen atom, a linear or branched C 1 to C 20 alkyl group, a linear or branched C 1 to C 20 alkoxy group, an amino acid radical, a mono- or polyhydroxylated acid radical or a C 5 to C 12 aryl or heteroaryl radical,
  • radical polymerization being carried out in the presence of at least one molecule of a poly- or oligosaccharide under pH and atmosphere conditions unfavorable to the presence and/or to the generation of anions in the reaction medium and in the presence of a sufficient amount of a suitable radical redox initiator.
  • the pH of the reaction medium is preferably adjusted to a value of less than 2 and more preferably of less than 1.5.
  • the particles correspond to the characteristics set out above.
  • freeze dryings are carried out without the addition of cryoprotective agent.
  • copolymers' obtained in examples 1, 2 and 3 are characterized in terms of size, stability and charge.
  • the Zeta potential obtained with the heparin-poly(isobutyl cyanoacrylate) particles is further from neutrality than that obtained with the dextran-poly(isobutyl cyanoacrylate) particles.
  • the content of polymer in the suspensions is determined by evaluation of the weight of the dry residue obtained after freeze drying a known amount of suspension purified by dialysis. To do this, an aliquot of purified suspension prepared according to example 1 or 2 is accurately weighed in a sample tube and then frozen to ( ⁇ 18° C.) before freeze drying for 48 h in a Christ Alpha 1-4 freeze dryer (Bioblock Scientific). The mass of lyophilizate is weighed and then related back to the mass of initial suspension.
  • the suspension of dextran-poly(isobutyl cyanoacrylate) copolymer obtained according to example 1 comprises 3.1 ⁇ 0.4% of copolymer (mass/mass).
  • the suspension of heparin-poly(isobutyl cyanoacrylate) copolymer obtained according to example 2 comprises 2.4 ⁇ 0.7% of copolymer (mass/mass).
  • the composition of the copolymers is evaluated by elemental analysis of the powders obtained by freeze drying the purified suspensions as is indicated above.
  • the dextran-poly(isobutyl cyanoacrylate) copolymer obtained according to example 1 comprises 20% (mass/mass) of dextran.
  • Teflon® collar with holes at 0°, 90° and 180°.
  • the size of the holes is adjusted in order to act as support for the optical fibers and the size of the Teflon® collar is adjusted to the glass tube in which the polymerization will be carried out.
  • the optical fibers are fitted to the collar in the 0° and 1800 positions for absorbance measurements.
  • the polymerization is carried out according to the protocol described in examples 1 to 3 in the glass tube with a diameter of 2 cm placed in a water bath at 40° C. and on which the Teflon® collar supporting the optical fibers connected to the spectrometer and to the light source is fitted.
  • the bubbling with argon is positioned so as not to interfere with the acquisition of the measurements.
  • the background noise of the spectrometer is recorded before the introduction of the acid solution of cerium(IV) ions (8 ⁇ 10 ⁇ 2 mol/l of cerium ammonium nitrate in 0.2 mol/l HNO 3 ).
  • the reference is recorded after the addition of the acid solution of cerium(IV) ions (8 ⁇ 10 ⁇ 2 mol/l of cerium ammonium nitrate in 0.2 mol/l HNO 3 ).
  • the recording of the polymerization kinetics is begun from the addition of the 0.5 ml of monomer. It is carried out by the quasi-instantaneous acquisition of an absorbence spectrum over a broad wavelength range (400-800 nm) every 30 seconds for 50 min.
  • the absorbances measured at the wavelength of 650 nm are used to plot curves of absorbance as a function of time, thus reflecting the kinetics of polymerization.
  • the reaction is continued with stirring at 40° C. for 50 min.
  • the reaction is halted and the flask is cooled under mains water.
  • the pH is adjusted with NaOH (1N) in order, after the addition of 6.25 ml of trisodium citrate dihydrate (1.02 mol/l), for it to arrive directly at a value of 7 ⁇ 0.5.
  • the mean hydrodynamic diameter of the particles of copolymers obtained is 291 ⁇ 1 nm.
  • 0.1375 g of dextran 70000 g/mol are dissolved in 8 ml of HNO 3 (0.2 mol/l) in a 20 ml screw-capped bottle with magnetic stirring at 20° C. After 10 minutes, 2 ml of acid solution of cerium ions (8 ⁇ 10 ⁇ 2 mol/l of cerium(IV) ammonium nitrate in 0.2 mol/l HNO 3 ) and then 0.5 ml of isobutyl cyanoacrylate are added. After 60 minutes, stirring is halted. The pH is adjusted with NaOH (1N) in order, after the addition of 1.25 ml of trisodium citrate dihydrate (1.02 mol/l), for it to arrive directly at a value of 7 ⁇ 0.5. The mean hydrodynamic diameter of the particles of copolymers obtained is 393 ⁇ 5 nm.
  • Frozen normal plasma is defrosted in a water bath at 37° C. and then placed in an ice tray.
  • the APTT reagent (Organon Teknica Corporation, Fresnes, France) is regenerated with 3 ml of sterile water.
  • a ⁇ fraction (1/40) ⁇ mol/1 CaCl 2 solution is prepared in Owren-Koller buffer (OKB) (Diagnostic Stago).
  • the suspensions of particles of copolymers are also diluted in the OKB to ⁇ fraction (1/100) ⁇ th and to ⁇ fraction (1/200) ⁇ th. 100 ⁇ l of each of the dilutions of the suspension are themselves diluted in 900 ⁇ l of normal plasma.
  • a clotting control is composed of 100 ⁇ l of OKB and 900 ⁇ l of normal plasma.
  • a bead is placed in each of the cells of the ST4 coagulometer (Diagnostica Stago) and then 100 ⁇ l of one of the samples prepared in the preceding stage and 100 ⁇ l of the APTT solution are introduced into the various cells. After incubating for 300 seconds at 37° C., 100 ⁇ l of the calcium chloride solution are added. The coagulometer measures the clotting times of the various samples in seconds. The results obtained for the control heparin solutions make it possible to draw up a calibration curve giving the activity of the heparin solution, expressed in IU/ml, as a function of the clotting time, expressed in seconds. The activity of the heparin associated with the copolymer particles is evaluated on the calibration curve from the clotting times measured for the suspensions.
  • the suspension comprising particles, prepared according to example 2, of heparin-poly(isobutyl cyanoacrylate) copolymers exhibit an anti-IIa activity of 329 ⁇ 28 IU/ml.
  • the suspension of copolymer particles is diluted to ⁇ fraction (1/50) ⁇ th, to ⁇ fraction (1/100) ⁇ th and to ⁇ fraction (1/200) ⁇ th in the OKB buffer and then to ⁇ fraction (1/10) ⁇ th in defrosted normal plasma as indicated above.
  • the clotting times are evaluated automatically on an ST1 coagulometer (Diagnostica Stago) automatically.
  • the anti-Xa activity of the suspension of particles of the heparin-poly(isobutyl cyanoacrylate) copolymers is 408 ⁇ 50 IU/ml.
  • a suspension, not purified by dialysis, of particles of copolymers is prepared according to example 2 with dextran 15-20000 g/mol.
  • the suspension is filtered through a 1.2 ⁇ m filter (Millipore® SLA P0 2550) and then purified by 2 dialyses of 2 hours against 1 l of osmosed water, followed by one dialysis of 2 hours against 1 l of phosphate buffer (Sigma ref. P 3813) (dialysis membrane: Spectra/Por® CE MWCO: 100000 regenerated for 30 min in osmosed water).
  • the suspension is placed in a dialysis bag (Spectra/Por® CE MWCO: 100000), regenerated beforehand for 30 min with osmosed water, and then dialyzed three times against 1 l of phosphate buffer for 2 hours.
  • the suspensions of grafted particles are recovered and can be stored at (+4° C.).
  • the grafting of the label can be demonstrated by electron paramagnetic resonance (EPR) spectroscopy.
  • EPR electron paramagnetic resonance
  • the suspension obtained is placed in a measuring cell of a Varian E-4 EPR spectrometer.
  • the spectrum obtained, presented in FIG. 3 indicates that the 4-amino-TEMPO has indeed been grafted to the dextran chains of the copolymer forming the particles and that it is 81% found under slow motion conditions and 19% found under fast motion conditions according to the Kivelson simulation (Kivelson D. J., Journal Chem. Phys., 1960, 33, 1107).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicinal Preparation (AREA)
US10/416,840 2000-11-17 2001-11-16 Block-structure copolymer consisting of a saccharide segment bound to at least a biodegradable hydrophobic segment, and corresponding particles Abandoned US20040028635A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR00/14900 2000-11-17
FR0014900A FR2816949B1 (fr) 2000-11-17 2000-11-17 Copolymere a structure sequencee compose d'un segment saccharidique lie a au moins un segment hydrophobe bioerodable, et particules correspondantes
PCT/FR2001/003619 WO2002039979A1 (fr) 2000-11-17 2001-11-16 Copolymere a structure sequencee compose d'un segment saccharidique lie a au moins un segment hydrophobe bioerodable, et particules correspondantes

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US (1) US20040028635A1 (fr)
EP (1) EP1355627A1 (fr)
AU (1) AU2002220793A1 (fr)
FR (1) FR2816949B1 (fr)
WO (1) WO2002039979A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060182807A1 (en) * 2002-09-17 2006-08-17 Christine Vauthier Copolymer and hemoprotein based novel compounds and uses thereof
US20100040883A1 (en) * 2001-12-19 2010-02-18 Mccarthy Stephen P Polysaccharide-containing block copolymer particles and uses thereof
US20100150994A1 (en) * 2006-12-01 2010-06-17 Anterios, Inc. Amphiphilic entity nanoparticles
US20100172943A1 (en) * 2006-12-01 2010-07-08 Anterios, Inc. Peptide nanoparticles and uses therefor
US20100285140A1 (en) * 2007-12-27 2010-11-11 Shoichi Shirotake Antimicrobial agent for gram-positive bacteria
US20110212157A1 (en) * 2008-06-26 2011-09-01 Anterios, Inc. Dermal delivery
US9062151B1 (en) 2012-09-21 2015-06-23 The United States of America, as represented by The Secretary of Agiculture Protein-cyanoacrylate nanoparticles that improve wetting property of materials
US10016451B2 (en) 2007-05-31 2018-07-10 Anterios, Inc. Nucleic acid nanoparticles and uses therefor
US10532019B2 (en) 2005-12-01 2020-01-14 University Of Massachusetts Lowell Botulinum nanoemulsions
US11311496B2 (en) 2016-11-21 2022-04-26 Eirion Therapeutics, Inc. Transdermal delivery of large agents

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FR2839517A1 (fr) * 2002-05-07 2003-11-14 Centre Nat Rech Scient Nouveaux agents tensioactifs biodegradables de type copolymeres amphiphiles constitues de segments hydrophobes et d'oligo et/ou polysaccharides
ES2311226T3 (es) 2004-05-05 2009-02-01 Firmenich Sa Copolimeros injertados biodegradables.

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US6881421B1 (en) * 1998-02-27 2005-04-19 Bioalliance Pharma S.A. Nanoparticles comprising at least one polymer and at least one compound able to complex one or more active ingredients

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US6881421B1 (en) * 1998-02-27 2005-04-19 Bioalliance Pharma S.A. Nanoparticles comprising at least one polymer and at least one compound able to complex one or more active ingredients

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110020227A1 (en) * 2001-12-19 2011-01-27 University Of Massachusetts Polysaccharide-containing block copolmer particles and uses thereof
US20100040883A1 (en) * 2001-12-19 2010-02-18 Mccarthy Stephen P Polysaccharide-containing block copolymer particles and uses thereof
US7763663B2 (en) * 2001-12-19 2010-07-27 University Of Massachusetts Polysaccharide-containing block copolymer particles and uses thereof
US20060182807A1 (en) * 2002-09-17 2006-08-17 Christine Vauthier Copolymer and hemoprotein based novel compounds and uses thereof
US10532019B2 (en) 2005-12-01 2020-01-14 University Of Massachusetts Lowell Botulinum nanoemulsions
US10576034B2 (en) 2005-12-01 2020-03-03 University Of Massachusetts Lowell Botulinum nanoemulsions
US20100172943A1 (en) * 2006-12-01 2010-07-08 Anterios, Inc. Peptide nanoparticles and uses therefor
US10758485B2 (en) 2006-12-01 2020-09-01 Anterios, Inc. Amphiphilic entity nanoparticles
US10905637B2 (en) 2006-12-01 2021-02-02 Anterios, Inc. Peptide nanoparticles and uses therefor
US10285941B2 (en) 2006-12-01 2019-05-14 Anterios, Inc. Amphiphilic entity nanoparticles
US9486409B2 (en) 2006-12-01 2016-11-08 Anterios, Inc. Peptide nanoparticles and uses therefor
US9724299B2 (en) 2006-12-01 2017-08-08 Anterios, Inc. Amphiphilic entity nanoparticles
US20100150994A1 (en) * 2006-12-01 2010-06-17 Anterios, Inc. Amphiphilic entity nanoparticles
US10016451B2 (en) 2007-05-31 2018-07-10 Anterios, Inc. Nucleic acid nanoparticles and uses therefor
EP2236143A4 (fr) * 2007-12-27 2011-01-05 Public Univ Corp Yokohama City Agent antimicrobien pour bactéries gram-positives
US20100285140A1 (en) * 2007-12-27 2010-11-11 Shoichi Shirotake Antimicrobial agent for gram-positive bacteria
US20110212157A1 (en) * 2008-06-26 2011-09-01 Anterios, Inc. Dermal delivery
US9062151B1 (en) 2012-09-21 2015-06-23 The United States of America, as represented by The Secretary of Agiculture Protein-cyanoacrylate nanoparticles that improve wetting property of materials
US11311496B2 (en) 2016-11-21 2022-04-26 Eirion Therapeutics, Inc. Transdermal delivery of large agents

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EP1355627A1 (fr) 2003-10-29
WO2002039979A1 (fr) 2002-05-23
FR2816949A1 (fr) 2002-05-24
FR2816949B1 (fr) 2003-11-28
AU2002220793A1 (en) 2002-05-27

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